Type-2 inflammation mediates olfactory loss in Chronic Rhinosinusitis: mechanisms and therapeutic opportunities

2 型炎症介导慢性鼻窦炎的嗅觉丧失：机制和治疗机会

• 批准号: 10219804
• 负责人: Bruce K Tan
• 金额: $ 59.41万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-23 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219804
• 关键词: ATP12A gene; Accounting; Adrenal Cortex Hormones; Affect; Agonist; Anosmia; Antibiotics; Biological Markers; CCL26 gene; Cell Line; Cells; Chemicals; Chronic Sinusitis; Clinical; Clinical Research; Data; Diagnostic radiologic examination; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Endoscopy; Enrollment; Environment; Eosinophilia; Epithelial Cells; Food; Food Selections; Formulation; Gene Expression; Genes; Genetic; H(+)-K(+)-Exchanging ATPase; Health; Human; Impairment; In Vitro; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Interleukin-5; Investigator-Initiated Research; Ion Pumps; Knock-out; Laboratories; Lansoprazole; Longitudinal Studies; Mass Spectrum Analysis; Measures; Mediating; Medical; Mentors; Methods; Mucosal Immunity; Mucositis; Mucous Membrane; Mucous body substance; Nasal Epithelium; Nasal Polyps; Nose; Olfactory dysfunction; Operative Surgical Procedures; Oral; Otolaryngology; Pathogenicity; Pathway interactions; Patient Self-Report; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Physicians; Placebos; Plasma; Porifera; Principal Investigator; Proton Pump; Proton Pump Inhibitors; Publishing; Quality of life; Randomized; Recurrence; Repeat Surgery; Research Project Grants; Risk; Sampling; Scientist; Severities; Sinus; Smell Perception; Structure of mucous membrane of nose; Surgeon; Symptoms; Testing; Therapeutic; Time; Tissues; Training; Translating; Translations; United States; United States National Institutes of Health; Universities; Visit; X-Ray Computed Tomography; airway epithelium; airway inflammation; airway surface liquid; base; chemokine; chronic rhinosinusitis; cost; cytokine; dosage; efficacy testing; eosinophil; eosinophilic inflammation; experience; experimental study; improved; increased appetite; inhibitor/antagonist; interest; novel; novel therapeutic intervention; novel therapeutics; phase II trial; professor; response; small molecule; transcriptome sequencing

Project Summary This is a request to the NIH for an Investigator-Initiated Research Project Grant (R01) for Bruce K. Tan, MD, MS, Assistant Professor of Otolaryngology at Northwestern University. The sense of smell in humans is pivotal for stimulating appetite, guiding food selection, avoiding spoiled foods and noxious chemicals, and enhancing overall quality of life. Unfortunately, many patients with chronic rhinosinusitis (CRS) suffer from extended periods of smell loss despite medical and surgical treatment. We further find that patients with type 2 inflammation of the nasal mucosa are more frequently and severely affected by smell loss before and after sinus surgery. CRS patients with type 2 inflammation are also more likely to experience recurrence of their symptoms and require repeated surgery. The Principal Investigator is a surgeon-scientist whose clinical interests focus on CRS patients but has completed extensive mentored training in mucosal immunity. This proposal seeks to translate a recent novel discovery in our laboratory that found that airway epithelial cell responses to IL-4 and -13, critical type 2 cytokines causing the most severe forms of chronic sinusitis, require action of an ion pump called the non-gastric H+/K+ATPase. Specific experiments will: (1) evaluate mechanisms by which the non-gastric H+/K+ATPase causes airway inflammation using drug inhibitors and genetic knockout cell lines; (2) evaluate how to use smell loss to accurately identify patients with active type 2 inflammation after sinus surgery; and (3) perform clinical studies to find out how to effectively use proton pump inhibitors to reduce airway eosinophilic inflammation and test whether they can reduce type 2 inflammation and improve smell function in patients with CRS. If successful, these studies will firmly establish a novel mechanism that disrupts the airway barrier in type 2 inflammatory conditions. Additionally, the results of this study may identify less invasive methods to identify type 2 inflammation in the nasal airway. Finally, the clinical studies may discover new drugs to treat persistent type 2 inflammation and smell loss in patients after sinus surgery- problems for which there are currently no effective medical treatments.

项目摘要 这是对NIH的一项请求，要求为布鲁斯·K·谭医学博士提供研究人员发起的研究项目拨款(R01)。 西北大学耳鼻喉科助理教授。 人类的嗅觉对于刺激食欲、指导食物选择、避免变质食物至关重要。 和有毒化学物质，并提高整体生活质量。不幸的是，许多慢性病患者 鼻-鼻窦炎(CRS)尽管接受了内科和外科治疗，但气味丧失的时间延长。我们 进一步发现，患有2型鼻黏膜炎症的患者更频繁、更严重 受鼻窦手术前后嗅觉丧失的影响。患有II型炎症的CRS患者也更多 可能会出现症状复发，需要反复手术。首席调查员是 外科医生-科学家，其临床兴趣集中于CRS患者，但已完成广泛的指导 粘膜免疫方面的培训。这项提议旨在将我们实验室最近的一项新发现转化为 发现呼吸道上皮细胞对IL-4和IL-13的反应最为严重的是关键的2型细胞因子 各种形式的慢性鼻窦炎需要一种称为非胃H+/K+ATPase的离子泵的作用。特定的 实验将：(1)评估非胃H+/K+ATPase引起呼吸道的机制 使用药物抑制剂和基因敲除细胞系进行炎症反应；(2)评估如何利用嗅觉丧失来 准确识别鼻窦手术后活动性2型炎症的患者；以及(3)进行临床研究 了解如何有效地使用质子泵抑制剂来减少气道嗜酸性炎症，并进行测试 是否能减轻CRS患者的II型炎症和改善嗅觉功能。如果成功， 这些研究将坚定地确立一种新的机制，即在2型炎症中破坏呼吸道屏障。 条件。此外，这项研究的结果可能会识别出侵入性较小的方法来识别2型 鼻腔内发炎。最后，临床研究可能会发现治疗持续性2型糖尿病的新药。 鼻窦手术后患者的炎症和气味丧失--目前尚无有效的治疗方法 医疗服务。